Field of the Invention
The present invention relates generally to the field of therapeutics for hemostatic disorders.
Background Art
While plasma-derived and recombinant clotting factor products allow hemophilia patients to live longer and healthier, hemophilia still remains one of the most costly and complex conditions to manage. The cost of clotting factor products exceeds $50,000 a year per patient. See Blankenship C. S., Biotechnol. Healthc. 2008, 5(4): 37-40. According to the National Heart, Lung, and Blood Institute, National Institute of Health (NIH), approximately 18,000 people in the U.S. have hemophilia, and 400 babies are born with the disease each year. Morbidity & Mortality: 2012 Chart Book on Cardiovascular, Lung and Blood Disease, page 5, National Heart, Lung, and Blood Institute, NIH. Due to its complexity, this chronic disease requires a special therapeutic management process for doctors, pharmacies, and patients. Clinicians often assess lifestyle, psychosocial requirements, and the home environment when evaluating a patient's or guardian's ability to provide adequate care.
In hemophilia, blood clotting is disturbed by a lack of certain plasma blood clotting factors. Hemophilia A, the most common form of hemophilia, is caused by Factor VIII deficiency. Hemophilia B is caused by decreased synthesis of Factor IX protein or synthesis of defective Factor IX having reduced activity. Treating hemophilia involves replacing missing or defective clotting factor with recombinant or plasma-derived FVIII or FIX. For patients who have developed antibodies against recombinant or plasma-derived FVIII or FIX, Factor VII can be used as a bypass therapy. Commercially available clotting factors are usually administered by peripheral intravenous injection. However, for patients with small veins or children who require frequent injections, clotting factors can be administered by a central venous access device. See Blankenship C. S., Biotechnol. Healthc. 2008, 5(4): 37-40.
Many biologics including clotting factors are administered based on patient body size. Body sized-based dosing is assumed to minimize inter-patient variability in pharmacokinetics (PK). Currently, three FIX products are approved by the Food and Drug Administration (FDA). The first, BENEFIX®, is a recombinant FIX product marketed by Pfizer. The second and third products are plasma-derived FIX products, ALPHANINE® marketed by Grifols and MONONINE® marketed by CSL Behring. According to their labels, these three products are dosed based on individual body weight. In particular, BENEFIX® is supplied as a lyophilized powder in five different dosages: 250 IU, 500 IU, 1000 IU, 2000 IU, and 3000 IU. MONONINE® is supplied as a single dose vial with Sterile Water for Injection at 500 IU and 1000 IU. ALPHANINE is supplied in lyophilized form as single doses at 500 IU, 1000 IU, and 1500 IU. The FIX dose required for each patient is calculated based on the formula:Number of factor IX IU required (IU)=Body Weight (kg)×Desired Factor IX Increase (% or IU/dL)×Reciprocal of Observed Recovery (IU/kg per IU/dL)  (A)
Several Factor VIII products are also commercially available, which include recombinant FVIII products (ADVATE® and RECOMBINATE® marketed by Baxter, KOGENATE® FS marketed by Bayer, HELIXATE® FS marketed by CSL-Behring, and XYNTHA® and REFACTO® marketed by PFIZER) and Plasma-derived FVIII products (HEMOFIL-M® marketed by Baxter, MONARC-M® by American Red Cross, and MONOCLATE-P® marketed by CSL Behring). The required FVIII dose for each patient is calculated using the following formula:Number of factor FVIII IU required (IU)=Body Weight (kg)×Desired Factor FVIII Increase (IU/dL or % of normal)×0.5(IU/kg per IU/dL)  (B)
A Factor VII product, NOVOSEVEN® marketed by Novo Nordisk, is also commercially available. The dosages of NOVOSEVEN® are also calculated based on body weight: 90 g/kg bolus injection every two hours for Hemophilia A or B with inhibitors, 15-30 g/kg every 4-6 hours for congenital FVII deficiency, or 70-90 g/kg every 2-3 hours for acquired hemophilia. See NOVOSEVEN® label, page 1, January 2010, version 3, Novo Nordisk A/S.
However, administering clotting factors via body weight-based dosing can be inconvenient and costly for patients. The invention as described herein provides improved clotting factor-dosing strategies.